an investigational drug for the treatment of -Induced

October 2012 Cautionary Statement Regarding FdForward-LkiSttLooking Statement s

In order, among other things, to utilise the 'safe harbour' provisions of the US Private Securities Litigation Reform Act 1995, we are providing the following cautionary statement: This presentation contains certain forward-looking statements with respect to the operations , performance and financial condition of the Group. Although we believe our expectations are based on reasonable assumptions, any forward-looking statements, by their very nature, involve risks and uncertainties and may be influenced by factors that could cause actual outcomes and results to be materially different from those predicted. The forward-looking statements reflect knowledge and information available at the date of preparation of this presentation and AstraZeneca undertakes no obligation to update these forward-looking statements. We identify the forward-looking statements by using the words 'anticipates', 'believes', 'expects', 'intends' and similar expressions in such statements. Important factors that could cause actual results to differ materially from those contained in forward-looking statements, certain of which are beyond our control, include, among other things: the loss or expiration of patents, marketing exclusivity or trade marks, or the risk of failure to obtain patent protection; the risk of substantial adverse litigation/government investigation claims and insufficient insurance coverage; exchange rate fluctuations; the risk that R&D will not yield new products that achieve commercial success; the risk that strategic alliances and acquisitions will be unsuccessful; the impact of competition, price controls and price reductions; taxation risks; the risk of substantial product liability claims; the impact of any failure by third parties to supply materials or services; the risk of failure to manage a crisis; the risk of delay to new product launches; the difficulties of obtaining and maintaining regulatory approvals for products; the risk of failure to observe ongoing regulatory oversight; the risk that new products do not perform as we expect; the risk of environmental liabilities; the risks associated with conducting business in emerging markets; the risk of reputational damage; the risk of product counterfeiting; the risk of failure to successfully implement planned cost reduction measures through productivity initiatives and restructuring programmes; the risk that regulatory approval processes for biosimilars could have an adverse effect on future commercial prospects; and the impact of increasing implementation and enforcement of more stringent anti-bribery and anti-corruption leg is la tion. No thing in this presen ta tion s hou ld be cons true d as a pro fit forecas t.

2 Introduction and Overview

Section Speaker Introduction Kathy Cantagallo naloxegol VP, Development

Overview of the Opioid Market Mike Gibbs VP Brand Marketing Naloxegol: Overview of the Mark Sostek, M.D. molecule and its development Executive Director, Development Overview and Summary Kathy Cantagallo naloxegg,ol VP, Develop ment Q&A

3 Introduction Key Facts

AstraZeneca and Nektar Therapeutics entered into an exclusive worldwide license agreement for naloxegol on 21 September 2009 . AstraZeneca has development and commercialization rights for naloxegol (previously NKTR-118). Nektar received an upfront 1 payment of $125m .

Naloxegol is a once a day oral, peripherally acting, μ- antagonist under investigation for the treatment of constipation as a side effect of prescription opioid pain medicines 2 (“opioid-induced constipation” or OIC). The core Phase III KODIAC program for naloxegol comprises four clinical studies which are designed to investigate the safety and efficacyyg of naloxegol for the chronic treatment of OIC in p atients 3 with non-cancer related pain: •We anticipate having high level results for the Phase III program in Q4 2012.

4 Opioid Market Overview Worldwide total opioid sales and volume*

Sales Standard Units ($mil) (mil) $15,000 39,500 $14,500

38,500 $14,000

37,500 $13, 500

$13,000 36,500

$12,500 35,500 MAT MAT MAT MAT MAT MAT MAT MAT MAT MAT Q2/08 Q2/09 Q2/10 Q2/11 Q2/12 Q2/08 Q2/09 Q2/10 Q2/11 Q2/12

Approximately 85% of opioid volume is long-term use (>30days)** Leading diagnoses for opioid use*** Chronic Back Pain Osteoarthritis Neuropathic Pain Cancer Pain Fibromyalgia (24)% (15)% (4)% (4)% (1)%

*Source: IMS MDART MAT-2Q12 **Source: NKTR-118 OIC Patient Quantitative Study, Mar-2010 US, UK, Ger, Fra, Can ***Source: IMS Medical Database, MAT @Q2012; based on Rxs by diag; other diags account for less than 1% each but add up to the other 50%; US, UK, Ger, Fra, Can The opioid market is dominated by US, Canada, France, Germany and UK*

Sales Standard Units ($mil) (mil)

ALL ALL OTHER OTHER 19.5% JAPAN 21. 0% JAPAN 0.4% 3.3% U. S. CANADA 49.3% CANADA 4.8% 4.4% U. S. 54.3% FRANCE 4.8% FRANCE 5.1% UK UK 5.4% 14.0%

GERMANY 8.4% GERMANY N = $14.8 bn5.3% N = 39.5 bn

*IMS MDART MAT-2Q12. Opioid Induced Constipation Mechanism of Opioid-Induced Constipation Although highly effective in the control of pain, the use of is associated with a key side effect - constipation1 – affecting Opioids bind to μ-opioid receptors in GI tract 40-50% of patients.2 GI motility, secretion, fluid absorption, and blood Constipation can negatively impact patient flow are affected quality of life3 and may result in patients avoiding or discontinuing pain therapy with Colonic transit delayed strong opioids, compromising effective analilgesia.1341,3,4 Sphincter tone increases OIC is often overlooked and inadequately Defecation inhibited managed.5,6,7 Whilst conventional can be used in conjunction with opioids to alleviate OIC symptoms, they do not treat the cause of the problem3 and often do not achieve the desired treatment outcome. 1,8

1Bell TJ et al . Pain Medicine. 2008 6 Tittle Met al. Am J Crit Care. 1994 2Yuan CS et al. 2005 Handbook of Opioid Bowel Syndrome 7 Pappagallo M. Am J Surg. 2001 3 Panchal SJ et al. Int J Clin Pract. 2007 8 Holzer Regulatory Peptides 155 (2009) 11-17. 4 Thorpe DM. Curr Pain Headache Rep. 2001 8 5 McMillan et al. Cancer Nurs. 2000 The Opioid Induced Constipation (OIC) opportunity

Of the $14.8 billion global opioid market, five markets $14.8 account for ~80% of total unit volume: US (49%), UK (14%), Germany (5%), Canada (5), France (5%).1 PCPs and Billion Pain Managgpement Specialists comp rise the maj jyority of prescribers in these markets.2

In these five markets, there are 69 million patients taking 69 opioids for chronic pain (>30 days treatment) .3 For these chronic pain opioid users, opioid induced constipation Million (OIC) is the most common side effect. 4, 5

28-35 Approximately 40–50% (28-35 million) patients taking 1, 2, 3 Million* opioids for long-term pain develop constipation.

11-18 About 40–50% (11-18 million) of those OIC sufferers achieve th e d esi red t reat ment out comes with current Million* options that include OTC and Rx laxatives.6, 7

1 IMS Health MIDAS MAT-2Q12 2 IMS Health NPA MAT-2Q12, Cegedim MAT-2Q11) 3IMS patient level data MAT-2Q09IMS patient level data MAT-2Q09 4 Panchal, S et al. Opioid-Induced Bowel Dysfunction: Prevalence, Pathophysiology and Burden. Int J Clin Pract. 2007;61(7):1181-1187. 5 Reimer, K et al. Meeting the Challenges of Opioid-Induced Constipation in Chronic Pain Management – A Novel Approach. Pharmacology. 2009;83:10–17. 6 Pappagallo, M. (2001). Incidence, prevalence, and management of opioid bowel. 9 dysfunction. Am J Surg 182(5A Suppl), 11S−18S. 7 Holzer Regulatory Peptides 155 (2009) 11-17. *Number of patients in major opioid markets Competitive landscape for OIC

Peripherally Acting mu-Opioid Receptor Antagonists: RELISTOR ( bromide) SQ - Salix/Progenics • Indicated for OIC in patients with advanced medical illness who are receiving palliative care, when response to therapy has not been sufficient • Introduced in 2008 RELISTOR (methlynaltrexone bromide) SQ - Salix/Progenics • ItitdfiInvestigated for use in non-chihronic non-cancer paititithOICin patients with OIC • CRL July 2012 RELISTOR (methlynaltrexone bromide) Oral - Salix/Progenics • Pre-registration (formerly CB-5945) – Cubist • Phase 2 complete, Phase 3 anticipated EOY 2012 TD-1211 – Theravance • Phase 2 recruitment compp;leted; seeking gp partner to commence Phase 3 (formerly S297995) – Shionogi • Phase 2b recruitment delays; Phase 3 start anticipated 2013 ______Amitiza () Oral – Sucampo [chloride channel activator] • Approved for Chronic Constipation • sNDA for Opioid Bowel Disease (OBD) filed July 2012, granted fast track review for potential launch Q2 2013 OIC from a Customer Perspective: Patients, Physicians, Payers

11 Source: Patient quotes are from qualitative interviews with US OIC patients, August 2012. HCP quotes are from qualitative interviews with US HCPs, October 2009.; Payor quote from qualitative interviews with US payors, January 2012. Naloxegol An overview of the molecule and development Naloxegol MhiMechanism of fAti Action • Opioids bind to mu-opioid receptors located throughout the body (including bibrain an d gu t)1

• When opioids bind to mu-opioid receptors in the brain the outcome is pain relief1

• When opioids bind to mu-opioid receptors in the GI tract/gut the outcome is decreased GI motility which may lead to constipation1, 2, 3, 4 Naloxegol-chemical structure • Naloxegol is a PEGylated mu-opioid antitthtblkthiidtthtagonist that blocks the opioid at the receptor site in the gut.5

• Due to PEGyyplation, uptake of naloxe gol across the Blood-Brain Barrier is limited6

1 Gutstein HB et al Goodman & Gilman’s; The Pharmacological Basis of Therapeutics, 10th ed. New York, McGraw-Hill 2001; 569-620 2Holzer P. Opioid receptors in the gastrointestinal tract. Regul Pept. 155(1-3); 2009; 11-17 3Kurz A and Sessler DI. Opioid-induced bowel dysfunction: patpathophysiologyhophysiology and potentipotentialal new therapies . Drugs 63(7); 2003; 649-671 4DeHaven-Hudkins DL et al. The involvement of the u-opioid receptor in gastrointestinal pathophysiology: Therapeutic opportunities for antagonism at this receptor. Pharmacology & Therapeutics 117; 2008; 162-187 5Neumann et al. poster 27 presented at 18th Annual Clinical Meeting of the American Academy of Pain Management; September 27-30, 2007; Las Vegas, NV 6Eldon et al. poster 28 presented at 18th Annual Clinical Meeting of the American Academy of Pain Management; September 27-30, 2007; Las Vegas, NV 13 NKTR-118: Phase II Study 07-IN-NX003 Design

~10 Days 14 Days7 Days 28 Days 14 ±2 Days

Single-Blind Double-Blind Placebo Run-In Active Initial OIC Screening Screening (<3 SBMs/wk) Follow-Up Single-Blind Double-Blind Placebo Run-In Placebo

Randomization

Daily oral dosing for 28 days 5, 25, and 50 mg QD cohorts (n=28 placebo and n=28 active patients planned per cohort) in sequence with an independent Dose Escalation Safety Committee review prior to dose escalation Webster et al. Am J Gastroenterol 2009; 104 ( Suppl 3) : S 466

14 Summary of Patient Demographics and Dispp(osition (Phase II Study)

5 mg QD 25 mg QD 50 mg QD Total RdRandom idized Pbo NKTR- Pbo NKTR- Pbo NKTR- N = 208 118 118 118 (N=36) (N=35) (N=29) (N=31) (N=39) (N=37) N=207 Age (years) Mean 48.0 50.5 51.2 51.8 48.7 51.4 50.2 (SD) (12.2) (12.7) (12.8) (11.1) (10.2) (11.4) (11.7) Efficacy Early termination Prior to double Sex Evaluable blind treatment N = 185 N = 14 Female 23 22 19 16 24 25 129 (63.9%) (62.9%) (65.5%) (51.6%) (61.5%) (67.6%) (62.3%) Opioid Stratum >100 23 21 14 18 19 21 116 Early termination MEU* (63.9%) (60%) (48.3%) (58.1%) (48.7%) (56.8%) (56%) During double blind treatment *MEU = Equivalent Units N = 32**

**Drop-outs During Double Blind Treatment 5 mg 25 mg 50 mg Webster et al. Am J Completed Early termination Gastroenterol 2009; 104 PBO 5 0 6 Study During follow up ( Suppl 3) : S 466 NKTR-118 5 2 14 N = 160 N = 2 15 Phase II Study Primary Efficacy Endpoint: Change from Baseline in Spontaneous Bowel Movements (SBMs/week) Week 1 of Double Blind Treatment P = NS P = 0.002 P = 0.0001 5

4 4.4 5 mg: 4.4 SBM/week

M (SE) 25 mg: 5.0 SBM/week 3 3.6 50 mg: 6.0 SBM/week

ge in SB 2 nn Significant over 4 -wk 2.6 1.9 1.9 treatment period for Cha 1.8 1 25 mg (P=0.002) and 50 mg (P< 0 .0001) Placebo 0 NKTR-118 5 mg 25 mg 50 mg

N = 72 N = 60 N = 76 Webster et al. Am J P-values based on a Gastroenterol 2009; 104 16 Wilcoxon Test Once daily oral dosing ( Suppl 3) : S 466 Phase II Study Median Time (hrs) to First Spontaneous Bowel Movements

NS P = 0.001 P < 0.002 60

MM 48.6 50 44.9 rst SB

ii 40 28.2 Placebo 30 Naloxegol rs) to F

hh (NKTR-118) 20

Time ( 10 6.2 6.6 292.9 0 5 mg 25 mg 50 mg

Webster et al. Am J Gastroenterol 2009; 104 ( Suppl 3) : S 466 P-values based on a log rank test 17 Safety: Most Common Adverse Events ( Phase II) (>10%, any grade)

5 mg QD 25 mg QD 50 mg QD % of Patients Placebo NKTR-118 Placebo NKTR-118 Placebo NKTR-118 Reporting at (N=32) (N=33) (N=27) (N=30) (N=37) (N=35) Least 1 Adverse Event Abdominal Pain 3 3 7 30 0 17

Nausea 3 15 19 13 8 20

Diarrhea 16 15 4 13 5 31

Vomiting 60413511

Upper 0 18 4 10 5 29 Abdominal Pain

• No treatment related SAEs at 5 or 25 mg/day, as assessed by investigator • Total 3 SAEs NGL and 2 for placebo • One patient hospitalized overnight for abdominal cramping at 50 mg/day (SAE)

Webster et al. Am J Gastroenterol 2009; 104 (Suppl 3) : S 466; adapted 18 Summary of Key Outcomes in Phase II study

• Primary Endpoint • Statistically Significant difference versus placebo for 25 and 50 mg doses in change from Baseline in Spontaneous Bowel Movements (SBM) at week 1

• Secondary Safety Endpoints - Patient Pain Assesment • No statistically significant difference compared with placebo for any dose, as measure by daily NRS pain scores - Opioid Dosing Requirement • No statistically significant increase in mean daily opioid dose for 25 and 50 mg doses compared with placebo - Adjudicated events (MSOWS) • None for any NGL dose

• Safety Findings - Most common side effects GI in nature

19 Naloxegol core KODIAC Phase III Clinical Program

2011 2012 2013 2014 2015

PH3 ID

KODIAC 4 (Pivotal) Stud y C ount ri es US KODIAC 7 (DBE) H2 EU Australia KODIAC 5 (Pivotal) PLANNED SUBMISSION KODIAC 8 (LTS)

Primary Endpoint - Percentage of responders over 12 weeks (Responder: >3 SBMs/week with improvement of > 1 over baseline for 9 out of 12 weeks and 3 out of the last 4 weeks)

Key Secondary Endpoints - 1) Laxative Inadequate Responders (LIR) subgroup % responders over 12 weeks 2) Median time (hours) to first post dose laxation 3) Mean number of days/week with SBM

20 Phase III (Study 4 and 5) Design

5 to 14 Days 14 Days 12 Weeks 14 Days

Double-Blind Active 12.5 mg (Visits 3 to 8)

Initial Screening OIC Confirmation Double-Blind Active Follow-up (Visit 1) (Visit 2) 25 mg (Visit 9) (Visits 3 to 8)

Double-Blind Placebo (Visits 3 to 8)

Randomization (Visit 3) N= 210/arm

Adapted from Clinical trial.gov 21 Phase III Long Term Safety Study (8) Design

Randomization 52-week treatment period

Patients from study 25 mg QD open-label D3820C00005 or study D3820C00007 can be randomized without a 2-week follow-up period screening period or an OIC confirmation period Usual Care OIC therapy (Physician’s choice) open-label New patients enter after a screening period and an OIC Confirmation period

2:1 randomization; NGL 560 patients, Usual Care 280 patients (approximate)

Adapted from Clinical trial.gov 22 Naloxegol Key Facts Summaryyy Key Facts

• Naloxegol is a once a day oral, peripherally acting, μ-opioid receptor antagonist under investigation for the treatment of Opioid-Induced Constipation (OIC).

• OIC may occur wh en opi oid s bin d to op io id recep tors in gas tro in tes tina l tract causing decreased GI motility.

• Phase II results indicate naloxegol at doses of 25 and 50 mg/day: - met the primary efficacy endpoint - was not associated with changes in opioid-mediated analgesia compared with placebo , while - most common side effects were GI related.

• Phase III clinical development for naloxegol started in March 2011. We anticipate having high level efficacy results in 4Q 2012. Summary Key Facts

• Global opioid market:

• Of the $14.8 billion global opioid market, five markets account for ~80% of total unit volume: US (49%), UK (14%), Germany (5%), Canada (5), France (5%). • In these five markets there are 69 million patients taking opioids for chronic pain (>30 days treatment). For these chronic pain opioid users, OIC is the most common side effect.

• Approximately 40–50% (28-35 million) patients taking opioids for long-term pain develop constipation. • About 40–50% (11-18 million) of those OIC sufferers achieve the desired treatment outcomes with current options that include OTC and Rx laxatives. Naloxegol Q&A